Autosomal dominant polycystic kidney disease (ADPKD) is an important cause of end-stage renal disease. Male gender is a risk factor for faster loss of renal function, but mechanisms of gender-related risk are not well understood. There is similar sexual dimorphism in the Han:SPRD rat model of ADPKD, in that females are relatively protected. Endocrine ablation studies in this model confirm the deleterious effect of androgens, and the protective effects of estrogen (17b-estradiol, E2). Clinically, use of estrogen therapy is limited by adverse endocrine and cardiovascular effects. Novel estradiol metabolites, including 2- methoxyestradiol (2-ME) and its precursor 2-hydroxyestradiol (2-OHE), provide many of the beneficial actions of E2. Since they have minimal affinity for the estrogen receptor, they appear safer for clinical use. Preliminary data indicate limitation of renal cyst growth and development by 2-OHE (>2-ME) in male Han:SPRD rats, and offer clues as to mechanisms of protection which will be explored in this grant. 2-OHE therapy was found to be associated with decreased renal tubular epithelial cell (RTE) apoptosis and proliferation;decreased renal expression of hypoxia-inducible factor-1a;increased expression of p21;and reduced expression of the mammalian target of rapamycin (mTOR), in cystic male kidneys. Hypotheses: (1) 2-OHE limits cystic growth and development of tubulointerstitial fibrosis by inhibition of angiogenesis;suppression of RTE proliferation;and/or induction of RTE apoptosis. These effects relate, in part, to modulation of the p21, Akt, and mTOR signaling systems. (2) 2-OHE limits cystic growth and development of tubulointerstitial fibrosis in genetically dissimilar models: the PCK rat and Pkd2 mouse models, by limiting RTE proliferation and apoptosis, and/or angiogenesis. Methods: Complementary in vivo and in vitro approaches will be used to explore protective mechanisms of 2- OHE, and interactions with the p21, Akt, and mTOR pathways, in the Han:SPRD rat model. Protective effects of 2-OHE will also be tested in the PCK rat and Pkd2 mouse models. Significance: These studies will investigate important mechanisms underlying sexual dimorphism in progression of ADPKD. Identification of clinically acceptable pharmacologic treatments to slow the progression of disease is the ultimate goal. PUBLIC HEALTH RELEVANCE: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of kidney failure, and males are more seriously affected than females. Novel metabolites of estrogen appear to slow progression of ADPKD in a male rat model, without the serious side effects seen with estrogen therapy. Identification of the mechanisms by which these drugs protect the kidney may enable us to devise new pharmacologic approaches, which are safe and effective in slowing the progression of clinical kidney disease.